CAS INSIGHTSTMNEURODEGENERATIVEDISORDERS
Deciphering Nervous System Decline

Introduction
Neurodegenerative diseases represent a spectrumof disorders that are characterized by the
progressive destruction of cells and connections
that make up the nervous system. These conditions
are detrimental to the lives of millions of people
worldwide, ultimately leading to the collapse of
the neural networks that are required for human
function.1

Older age has been associated with an increased
risk of developing a neurodegenerative condition,and the rise in longevity over the past decades
has coincided with an increased incidence ofneurodegenerative disorders. With an increasing
aging population worldwide, effective treatment
and management of these conditions becomesparamount.6

Alzheimer’s disease (AD), Parkinson’s disease(PD), amyotrophic lateral sclerosis (ALS), multiple
sclerosis, and polyglutamine (polyQ) diseases all
belong to the neurodegenerative classification,
and we will delve deeper into specific conditions
throughout this report.2–5

It has been proposed that neurodegenerative
diseases are defined by a set of common
attributes, including pathological protein
aggregation, synaptic and neuronal network
dysfunction, aberrant proteostasis, cytoskeletal
abnormalities, altered energy metabolism, DNA
and RNA defects, inﬂammation, and neuronal cell
death (Figure 1).1,6–8

In people with neurodegenerative disorders suchas those aforementioned, cells of the nervous
system, called neurons, are progressively damaged
and destroyed, resulting in the breakdown of thecore communicative connections.1 Depending on
the specific disease, this degeneration can lead to
impaired memory, cognition, behavior, sensory,
and/or motoric performance.1 Neurodegenerative
diseases remain incurable, but certain disorders
can be treated to provide symptomatic relief,
improve quality of life, or limit disease progression.
Neuronal celldeath

In this report, we examine data from the
CAS Content CollectionTM, the largest humancompiled multi-disciplinary database of publisheddocuments and substances, to inform readers
about the latest advances in the managementof neurodegenerative disorders.

Pathological protein
aggregation

Synaptic and neuronal
network dysfunction

Altered energy
homeostasis

Aberrant
proteostasis

Cytoskeletal
abnormalities

Neuro-inflammation

DNA and RNA
defects

Figure 1. Hallmarks of neurodegenerative diseases and relationships between them.1,6–8

Neurodegeneration: The global impact
Figure 2 depicts the worldwide prevalence of several notable neurodegenerative diseases, along with the number of
documents related to these diseases in the CAS Content Collection.9 Neurodegenerative disorders not only harm thelives of individuals with the condition, but can also be distressing for their loved ones.
Prion disease 0.00015%
FD 0.032%
LBD 0.035%
polyQ 0.005%
ALS 0.005%
MS
0.035%

PD
0.12%

FD 1.5%
LBD 0.2%
polyQ
ALS 6.4%
6.6%

Prion disease
1.9%

AD
39.7%

MS
16.4%
PD
27.1%

AD 0.68%

Worldwide prevalence (outer)
CAS Content Collection (inner)
Figure 2. Worldwide prevalence of major neurodegenerative diseases (outer circle) and distribution of the number of documents
related to those diseases in the CAS Content Collection (inner circle);9 ALS, amyotrophic lateral sclerosis; FD, frontotemporaldementia; LBD, Lewy body dementia; MS, multiple sclerosis; PD, Parkinson’s disease; polyQ, polyglutamine.

NEURODEGENERATIVE DISORDERS REPORT | 3

AD: The leading cause of dementia
Data from the World Health Organization suggests thatapproximately 50 million people live with dementia
worldwide, and AD accounts for 60–70% of cases. The
prevalence of AD increases with age, and the majorityof cases occur in individuals over 65 years old. As life
expectancy increases globally, the number of people
living with AD is expected to rise substantially in the
coming decades.10,11

AD is associated with abnormal deposits of specificproteins in the brain, specifically beta-amyloid
plaques and tau tangles.12 These deposits disrupt
communication between brain cells and lead to theireventual death, resulting in widespread neuronal loss
in brain regions critical for memory and cognitive
function, such as the hippocampus and cerebral cortex(Figure 3).12

Healthy brain

Alzheimer ’s brain

Axon(contains many
microtubules)

Amyloid beta
plaques

Tau protein
tangleStabilizing
tau protein

Healthy
microtubule

Disintegrating
microtubule
Figure 3. Pathological hallmarks of AD.

Individuals with AD experience a progressive decline
in cognitive function, memory loss, and changes
in behavior and personality, leading to a loss of
independence and ability to perform daily tasks.
As the disease progresses, individuals become
increasingly dependent on others for assistance withactivities of daily living. In the advanced stages of AD,
individuals may lose the ability to communicate verbally,recognize loved ones, or control movement. This meansthat people with AD often require round-the-clock carein a residential facility or at home with the assistanceof caregivers. Physical complications such as infections,falls, and malnutrition become more common withadvanced disease, contributing to further decline
in health.
Unsurprisingly, AD has a profound impact on
individuals, families, and society as a whole. The
economic impact of AD is substantial, including
direct medical costs for diagnosis, treatment, andlong-term care, as well as indirect costs associatedwith lost productivity and caregiver burden.

PD: The movement disorder
PD is the second most common neurodegenerative
disorder after AD.13 Its prevalence increases with age,with the majority of cases occurring in individuals over
the age of 60. Estimates of prevalence vary globally,
but it is generally reported to affect around 1–2% of
individuals over the age of 65.14 Prevalence rates tend tobe higher in industrialized regions, such as Europe andNorth America, compared to developing nations.15
PD primarily affects movement16–18 and is caused by
the gradual loss of dopamine-producing neurons ina section of the brain called the substantia nigra(Figure 4).19 Dopamine is a ‘neurotransmitter’ andis involved in coordinating movement. Dopamine
deficiency leads to the characteristic motor symptomsof PD, including tremors, bradykinesia (slowness of
movement), muscle rigidity, and postural instability.19
The effects of PD are not necessarily restricted to
impaired motor functions, and the condition can cause
cognitive decline, depression, and sleep disturbances. 20
While the exact cause of PD is not fully understood,
it is believed to involve a combination of genetic,
environmental, and age-related factors.16–18

Healthy brain pathway

Parkinson's disease
Aggregation of
α-synuclein proteins

Dopamine

Ub

Substantia
nigra

Ub

Lewy body
Impairment and lossof melanateddopaminergic neurons

Accumulationof Lewy bodies

Affected dopamine pathways
Affected during
early/mid stages:

Affected duringlate stage:

Nigrostriatal• Voluntary movement production

Mesocortical• Cognition• Memory and learning• Motivation

Mesolimbic• Emotion• Perception• Reward

Tuberoinfundibular• Sensory processing• Hormonal regulation• Maternal nurturing

Figure 4. Pathological hallmarks of PD.

NEURODEGENERATIVE DISORDERS REPORT | 5

PolyQ diseases: Rare conditions with a big impact
PolyQ diseases are a group of rare neurodegenerative disorders of which there are nine known types: Huntington’sdisease (HD); six spinocerebellar ataxias (SCA) types 1, 2, 3, 6, 7, 17; dentatorubral pallidoluysian atrophy (DRPLA);
and spinal and bulbar muscular atrophy (SBMA). 21
The incidence of polyQ disorders is around 1–10 cases per 100,000 people, 21,22 with HD and SCA3 having the highest
occurrence worldwide (Table 1). 23,24 DRPLA is predominantly documented in Japan25 , while the highest frequencies
of SBMA have been reported in Finland. 26,27 Although each disease is considered rare, together, polyQ diseases
constitute the largest group of neurodegenerative disorders that are caused by a single gene. 28
PolyQ disease

Mutated protein

Frequency worldwide

Clinical features/manifestations

HD

Huntingtin

3–7/100,000

Chorea, progressive cognitive decline,
psychiatric disorders

SCA1

Ataxin 1

1–2/100,000

Pyramidal signs, peripheral neuropathy,
motor control decline

SCA2

Ataxin 2

Unknown, common
in Cuba — 40/100,000

Slow eye movement, neuropathy,
hyporeﬂexia, tremor, chorea

SCA3 (Machado-Joseph
disease)Ataxin 3

1–9/100,000

Bulging eye, spasticity, fasciculations,sensory loss, amyotrophy, ataxia

SCA6

CACNA 1 P/
Q-type α 1A

0.02–0.31/100,000

Pure cerebellar signs

SCA7

Ataxin 7<1/100,000

Retinal degeneration

SCA17

TATA-binding
protein

0.16/100,000

Dystonia, dementia, involuntary
movements, hyperreﬂexia

DRPLA (Haw River
syndrome)

Atrophin 1

2.7/100,000

Ataxia, myoclonic epilepsy,
choreoathetosis, cognitive deficits

SBMA (Kennedy disease)

Androgen receptor

1–2/100,000 male

Weakness, muscular atrophy, bulbar palsy

SCAs

Table 1. PolyQ repeat expansion diseases.1, 23–25, 29–37

All of these conditions are characterized by a specific genetic abnormality that occurs in a unit called acytosine-adenine-guanine (CAG) trinucleotide repeat, leading to the production of proteins with an expanded
polyglutamine tract. 26 The resulting proteins are faulty, and the affected proteins differ between polyQ diseases interms of their function and location within the cell. Moreover, different brain regions and neuronal cell subtypes
are affected in each polyQ disease. 26 These genetic abnormalities mainly affect the central nervous system and areassociated with progressive degeneration, dysfunction, and the death of specific populations of neurons. 21,26,27,38,39
As the most common polyQ disorder, the pathological mechanism of HD has been defined. HD is caused by a polyQ
expansion in huntingtin protein, an important signal regulator in the nervous system. The primary hallmark is severe
deterioration of a section of the brain called the striatum, which is reduced to a fraction of its original size (Figure 5).40
Normal brain section

Huntington’s disease

Normal frontal hornsof the lateral ventricles

Enlargement of the frontal hornsof the lateral ventricles

Figure 5. Pathological hallmarks of HD.41

Landscape analysis of neurodegenerative disease research
Journal and patent activity
Currently, there are over 300,000, 220,000, and 50,000 scientific publications (mainly journal articles and patents)
related to AD, PD, and polyQ disorders in the CAS Content Collection, respectively. There has been a steady growthof these documents over the last few decades, with a 25–30% increase in the last three years across the three disease
subtypes (Figure 6A–F). Journal articles largely dominate, showcasing the intense research in the area.
AD
B

Patents

Number of documents
yearly growth, %Journals

15,00010,000

5,000

0
19

8

Alzheimer’s growth
Neurodegenerative growth
JRN/PAT Alzheimer's
JRN/PAT Neurodegenerative

7
6

14
12

5

10

4

8

3

6

2

4

1

2

0

90 992 994 996 998 000 002 004 006 008 010 012 014 016 018 020 022
1
1
1
2 2 2 2 2 2
1
2
2
2
2
2
2

16

19

Year

90 992 994 996 998 000 002 004 006 008 010 012 014 016 018 020 022
1 1 1 1 2 2 2 2 2
2 2 2 2 2 2 2Journal/Patent ratio

Number of documents

A 20,000

0

Year

PD
Journals

Number of documents
relative growth, %12,000D

Patents

10,000
8,000
6,000
4,000
2,000
0

8

6

8

6

4

4

2

2

0

90 92 94 96 98 00 02 04 06 08 10 12 14 16 18 20 22
19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20

Parkinson’s growth
Neurodegenerative growth
JRN/PAT Parkinson's
JRN/PAT NeurodegenerativeYear

90 92 94 96 98 00 02 04 06 08 10 12 14 16 18 20 22
19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20

Journal/Patent ratio

Number of documents

C 14,000

0

Year

PolyQ
3,000

JournalsF

Patents

Number of documents
yearly growth, %

2,500
2,000
1,500
1,000
500
0

19

90 992 994 996 998 000 002 004 006 008 010 012 014 016 018 020 022
2
1
2
2
1
1
2 2
2
1
2
2
2
2
2
2

Year

8
7
6

PolyQ growth
Neurodegenerative growth
JRN/PAT PolyQ
JRN/PAT Neurodegenerative

12
10
8

5

6

4
3

4

2
2

1
0

90 92 94 96 98 00 02 04 06 08 10 12 14 16 18 20 22
19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20

Journal/Patent ratio

Number of documents

E

0

Year

Figure 6. Yearly trend of the number of documents (journal articles and patents) related to AD, PD and polyQ diseases(A, C and E). Comparison between relative growth in the number of documents around each specific condition (dark bluebars) and all neurodegenerative diseases (light blue bars) in the CAS Content Collection (B, D and F). Orange and yellow
lines compare the journal/patent ratio for the specific condition to the journal/patent ratio for all neurodegenerative diseases,
respectively. JRN, journal; PAT, patent; JRN/PAT, journal/patent ratio.

NEURODEGENERATIVE DISORDERS REPORT | 7

Leading countries/regions
The United States, Japan, China, the United Kingdom, and Germany are among the leaders with respect to thenumber of published journal articles and patents related to AD, PD, and polyQ disorders. A significant proportionof patents come from the United States across all three conditions (Figure 7).
Journals

AD (A)

Belgium 1.1%

Iran 1.1%

Brazil 1.4%

Israel 1.0%

Switzerland 1.4%

Denmark 0.7%

S. Korea 2.7%
Sweden 2.7%
Others 19.0%

Spain 3.2%

France 3.1%

France 3.3%

Germany 4.8%

USA 17.4%

UK 3.6%

S. Korea
6.9%

Canada 3.7%

Germany 4.9%

Japan
7.0%

China 13.8%
Japan
6.0%

Journals
Poland 0.9%
Turkey 0.8%
Belgium 0.8%
Portugal 0.8%

Patents
Austria 0.3%
Taiwan 0.5%
Australia 0.7%
Netherlands 0.9%
Italy 1.2%
Belgium 1.4%
Sweden 1.5%
India 1.5%
Canada 1.6%
Spain 1.7%
Israel 1.8%
Denmark 2.0%

Brazil 0.2%
Portugal 0.2%
Poland 0.1%
Turkey 0.1%
Iran 0%

Switzerland 2.8%

Other 22.9%

S. Korea 2.5%

UK 3.4%

Spain 3.1%
India 3.3%

USA 33.7%

France 3.8%

France 3.4%

USA 11.8%

Germany 4.8%

UK 3.6%
Germany
Italy
5.6%

5.7%

Japan
5.7%

Japan 5.0%

China
10.9%

S. Korea
7.2%

Journals

China 12.5%
Others11.1%

PolyQ (C)

Netherlands 1.8%
Australia 1.9%

Patents

Spain 1.7%

India 1.3%

Spain 0.7%

S. Korea 1.3%

Taiwan 1.8%

Australia 0.3%

Taiwan 2.0%

Netherlands 2.3%

India 3.0%

Canada 2.3%

Italy 0.1%

S. Korea 2.4%

France 3.7%

France 3.5%

Canada 3.8%

Germany 3.6%

Italy 3.9%
USA 35.7%
China 5.4%

UK 3.8%
USA 49.6%

China
7.7%

Germany 5.7%
UK 5.8%China 15.0%
Others
8.9%

PD (B)

Denmark 0.9%
Iran 0.9%
Austria 0.9%
Taiwan 1.1%
Switzerland 1.2%
Israel 1.4%
Brazil 1.6%
Sweden 1.9%
Netherlands 2.2%
Australia 2.2%

Canada 4.0%

USA 33.5%
UK 3.4%

India 3.4%

Italy 4.7%

Italy 1.1%
Netherlands 0.8%
Australia 0.7%
Brazil 0.2%

Belgium 1.2%
India 1.3%
Sweden 1.3%
Israel 1.4%
Spain 1.5%
Canada 1.6%
Iran 1.6%
Denmark 1.7%
Switzerland 2.9%

Netherlands 2.1%

Australia 2.8%

Patents

Others
10.9%

Japan
13.4%

Japan
8.6%
Others
11.9%

Figure 7. Top countries/regions with respect to the percentage of AD (A), PD (B), and polyQ-related (C) journal articles (left) andpatents (right) in the CAS Content Collection.

The journals and institutions with the highest number of published articles across AD, PD, and polyQ disorders areshown in Table 2. Patenting activity in the field of neurodegenerative disorders is dominated by corporate players ascompared to academics; the leading organizations with regard to patent activity are also presented in Table 2.
Publication activity
Condition

Leading institutions

Leading journals

AD

The Alzheimer’s Disease Neuroimaging Initiative
University of California
Harvard Medical School
Chinese Academy of Sciences

Journal of Alzheimer’s Disease
Neurobiology of Aging
Neurology
PLoS OnePD

The National Institutes of Health
Capital Medical University
University of California
Juntendo University School of Medicine
University of Cambridge

Movement Disorders
Parkinsonism & Related Disorders
Neurology
PLoS One

PolyQ

University of British Columbia
Massachusetts General Hospital
University of California
University of Cambridge

Human Molecular Genetics
Movement Disorders
PLoS One
Neurology

Patenting activity
Condition

Commercial organizations

Non-commercial organizations

AD

Hoffmann-La Roche
AstraZeneca
Merck (MSD)
PfizerUniversity of California
French National Center for Scientific Research
Korea Institute of Science and Technology

PD

Hoffmann-La Roche
AstraZeneca
Merck
Neurosearch
PfizerUniversity of California
French National Center for Scientific Research
Korea Institute of Science and Technology
Massachusetts General Hospital
Johns Hopkins University

PolyQ

Hoffmann-La Roche
AstraZeneca
Merck
PfizerUniversity of California
General Hospital Corporation
Harvard College

Table 2. Leading organizations in the field of neurodegeneration in terms of number of published journal articles and patents.

NEURODEGENERATIVE DISORDERS REPORT | 9

Therapeutic approaches to neurodegeneration: Where are we now
and where are we going?
While there is currently no cure for any neurodegenerative conditions, various interventions can help
manage symptoms and support overall well-being. Treatment and management approaches toneurodegenerative disorders aim to alleviate symptoms, slow down disease progression, and improve
the quality of life for individuals affected by the condition.
There are a variety of medications that are approved by the U.S. Food and Drug Administration for
the treatment of neurodegenerative disorders, with many more in late-stage clinical trials. A numberof non-pharmacological strategies, such as regular physical activity, a balanced diet, healthy sleep
habits, and cognitive-behavioral therapy, have also been suggested to alleviate certain symptoms ofneurodegenerative diseases.
Pre-clinical development and clinical trials

Over the last 20 years, nearly 2,300 clinical trials
have been registered on clinicaltrials.gov for AD,
around 1,000 for PD, and about 480 for polyQ
diseases. Evaluation of therapeutic clinical trials in
the AD, PD, and polyQ settings has revealed thatthe majority of trials are not phased.

therapies. Clinical trials are currently dominatedby small molecules and monoclonal antibodies.

There are around 325 and 250 agents in preclinicaldevelopment for AD and PD, respectively, which
can broadly be categorized as small molecules,
antisense oligonucleotides, gene therapy, RNAinhibitor agents, monoclonal antibodies, and cell

Almost 45 substances are being researched anddeveloped preclinically for the treatment of polyQ
diseases. The vast majority of these are for thetreatment of HD, but substances for the treatmentof SCA are also in the development pipeline.
A wide range of therapies are being investigated,
including small molecules, protein degraders,
RNA therapeutics, gene therapy, and cell therapies,
amongst others.

A

B
160

180

Number of clinical trials

Number of clinical trials

200
160
140
120
100
80
60
40
20
0

03 04 05 06 07 08 09 10 011 12 13 14 15 16 017 18 19 20 21 22 23
20 20 20 20 20 20 20 20 2 20 20 20 20 20 2 20 20 20 20 20 20

Year

140
120
100
80
60
40
20
0

03 04 05 06 07 08 09 10 011 12 13 14 15 16 017 18 19 20 21 22 23
20 20 20 20 20 20 20 20 2 20 20 20 20 20 2 20 20 20 20 20 20

Year

C
Number of clinical trials

30

Dentatorubral-pallidoluysian atrophy
Spinal and bulbar muscular atrophy
Spinocerebellar ataxia
Huntington’s disease

25
20
15
10
5
0

03 04 05 06 07 08 09 10 011 12 13 14 15 16 017 18 19 20 21 22 23
20 20 20 20 20 20 20 20 2 20 20 20 20 20 2 20 20 20 20 20 20

Year
Figure 8. Number of clinical trials per year for AD (A), PD (B), and polyQ disorders (C).

Old tools for new tasks: The potential for drug repurposing in neurodegenerative disease
Since there is no cure for neurodegenerative diseases, drug repurposing studies have been intensely searching
to identify existing drugs that could be repositioned to treat conditions like AD and PD.42–48 As the pharmaceuticaldevelopment process is both time-consuming and costly, drug repurposing provides a chance to accelerate it byexploring the neurodegeneration-related effects of agents approved for other disorders. For AD alone, there are
50 widely discussed drugs for AD repurposing; 42–55 some examples of drugs commonly considered for repurposing
to AD and PD are shown in Table 3.
AD
Drug

CAS Registry Number®

Original indication

Lithium

7439-93-2

Bipolar disorder

Metformin657-24-9

Diabetes

Risperidone

106266-06-2

Antipsychotic

Nicotinamide

98-92-0

Vitamin

Atorvastatin

134523-00-5

Cardiovascular

Tamoxifen

10540-29-1

Anti-cancer

Tacrolimus

104987-11-3

Immunologic prophylaxis

Dronabinol

1972-08-3

Appetite stimulant, antiemetic

Riluzole

1744-22-5

Neurologic

PD
Drug

CAS Registry Number®

Original indication

Exenatide

141758-74-9

Type II diabetes

Telmisartan

144701-48-4

Hypertension

Triflusal

322-79-2

Thromboembolic prophylaxis

Levetiracetam

102767-28-2

Epilepsy

Vitamin B12

68-19-9

Vitamin B12 deficiencies

Pomalidomide

19171-19-8

Multiple myeloma

Exemestane

107868-30-4

Breast cancer, postmenopausal

Vilazodone

163521-12-8

AntidepressantTable 3. Examples of drugs commonly considered for repurposing to AD and PD.42–55

NEURODEGENERATIVE DISORDERS REPORT | 11

Hot topics in neurodegenerative research
Aging is the most widely explored concept in AD and PD, while pathogenesis, molecular mechanisms, and theclinical manifestations of diseases are the areas attracting the most attention in the polyQ setting (Figures 9 and 10).
A

B

Drug delivery systems 2%
Deep brain stimulation 2%

Aging: 115,000

Major concepts

Biomarkers 3%
Dopaminergic neuron 3%
Mitrochondria 3%β-Amyloid: 103,774

Oxidative stress 3%

Amyloid precursor proteins: 29,000

Aging 27%

Neuroinflammation 3%
α-Synuclein 3%

Blood-brain barrier: 7,062

Major concepts

Mutation 4%

Brain hippocampus: 28,000

Disease models 4%

Cerebral cortex: 11,000
Genotype: 6,319
Microglia: 9,377
Mutation: 9,913
Neurotoxicity: 6,852

Brain 8%Signal transduction 4%
Nerve degenration 4%

Neuron 8%

Dopamine 5%

Oxidative stress: 24,214

Gene 5%

Protein phosphorylation: 9,555

Substantia nigra 7%

Signal transduction: 18,000
Tau proteins: 24,000

Figure 9. Key concepts related to AD (A) and PD (B) explored in the scientific publications found in the CAS Content Collection.

Pathologicalproteinaggregation
Aggregation
inhibitors

DNA and RNA
defects

Chaperonebased
therapies

Neuronalcell death

Huntington’sdiseaseSCA2Autophagy
inducers

Aberrant
proteostasis

Spinocerebellar
ataxia

SCA3

Lipid

Cognitiveenhancers

Neuroinflammation

Dentatorubral
pallidoluysian
atrophy

SCA6PolymerDrug delivery
systems

Mitochondrial
dysfunction

Metal

Stem cells
Neuroprotective
agentsAmyloidplaques
Glial markersof neuroinflammation
Synaptic
markers
Cellularmarkers ofneurodegeneration

SCA1

Hallmarks

Diseases

Spinal & bulbar
muscular
atrophy

Synaptic andneuronal
network
dysfunction

SCA17

Pathogenesis
and molecularmechanisms

Cytoskeletal
abnormalities

PolyQ(Polyglutamine)
disorders

Biomarkers

ChoreaHeat shockproteinexpression
inducers
Proteostasis
modulators
Blood-brain
barrier
penetrants
Genetherapy
DiseasemodelsAdvancedimagingtechniques

SCA7

Therapeuticstrategies

Clinicalmanifestations

No. of documents> 3,000
1,000–3,000
500–1,000< 500

Expanded
polyQ track
Oligomerformation
Misfolding/aggregation
Proteindegredation
pathways
Abnormalconformationalchanges

Chromatin
structure andepigenetic
regulation

Cognitive
declineTranscriptional
dysregulation

Psychiatricdisorders

Toxicity /exitoxicity

AtaxiaPosttranslational
modification

Ubiquitin
proteasome
systemAutophagylysosomal
pathway

Phosphorylation

Proteolytic
cleavage
Acetylation
Sumoylation

Gaze palsy
Pyramidal
signs
Peripheral
neuropathy
Motor control
declineFigure 10. Conceptual mind map of the polyQ disease research area with indicationsof the number of documents in each subcategory.

Ubiquitylation
Palmitoylation

Targeting the hallmarks of aging could help to combat neurodegeneration
Aging is characterized by a time-dependent
gradual accumulation of cell damage and continual
physiological functional decline. As such, it is also
the most profound risk factor for many diseases.
Neurodegenerative diseases, such as AD, PD, and HD,
as well as sensory dysfunctions, all increase considerably
upon aging. 56–59

With an increasing global aging population and thesubsequent burden of healthcare for people withage-related diseases, intense efforts have been put
forth to understand and prevent the effects of aging.
The major cellular and molecular hallmarks of aging
have been identified, and their relationships to agerelated diseases, and especially to AD as one of themost common neurodegenerative disorders, have been
explored (Figure 11).60

A

B

Genomic instability: 185
Telomere attrition: 175
Epigenetic alterations: 855

Parkinson’s diseasehallmarks

Hallmarks of
aging

Loss of proteostasis: 1,022
Dysregulated nutrient sensing: 874

Aging hallmarks

Mitochondrial dysfunction: 4,878
Cellular senescence: 652
Stem cell exhaustion: 2,521
Altered intercellular communication: 1,782
Impaired autophagy: 4,191
Dysbiosis: 1,525
Chronic inflammation (inflammaging): 1,771

Loss of proteostasis

Calcium homeostasis
Synaptic dysfunction
Apoptosis

Mitochondrial
dysfunction

Dopaminergic
neurodegeneration

Inflammation

Environmental factors

Impairedproteinclearance

Genetic factors
α-Synuclein
accumulation

Epigenetic alterations
Stem cell exhaustion
Telomere attrition
Genomic instability
Altered intercellularcommunication
Cellularsenescence

Lipid metabolism disorders: 3,046

Figure 11. Correlation between primary aging hallmarks and AD as reflected by their co-occurrence in the documents in the
CAS Content Collection (A). Intersection between PD hallmarks and the hallmarks of aging (B).

NEURODEGENERATIVE DISORDERS REPORT | 13

Biomarkers
Biomarkers are objective measures that can be used to detect, diagnose, monitor disease progression, assess
treatment response, and predict outcomes in individuals with a specific condition.61 Biomarkers are the fastestgrowing concept related to AD, and there is significant interest in establishing reliable biomarkers in PD andpolyQ diseases.
Biomarker strategies for PD and polyQ diseases include:

PD

PolyQ

– Clinical biomarkers: Motor symptoms
and non-motor symptoms– Neuroimaging biomarkers: Dopaminetransporter imaging and functional andstructural magnetic resonance imaging (MRI)– Cerebrospinal fluid biomarkers: α-Synuclein,tau, and phosphorylated tau– Blood-based biomarkers: Blood-based
assays for α-synuclein levels and posttranslational modifications, biomarkers ofneuroinflammation– Genetic biomarkers: Genetic variants
associated with PD risk, identified throughgenome-wide association studies (GWAS)
and next-generation sequencing; pathogenic
monogenic mutations in genes such as SNCA,LRRK2, PARK2, and GBA– Peripheral biomarkers: Olfactory dysfunction,
alterations in gut microbiota composition andmetabolites– Mutant protein aggregates– Cerebrospinal fluid biomarkers:
Tau, neurofilament light chain, and specificfragments of huntingtin protein in HD– Peripheral biomarkers: Mutant protein
fragments, microRNAs, molecular signs ofoxidative stress– Neuroimaging markers: Structural changes
in the brain using MRI– Electrophysiological markers: Changes inelectrical activity in the brain or periphery– Biomarkers of oxidative stress andinflammation: Markers of lipid peroxidation,cytokine levels, or markers of glial activation– Metabolic biomarkers: Markers of energy
metabolism, mitochondrial function, or
metabolite levels in the brain or peripheral
tissues– Genetic modifiers: GWAS or whole-genome
sequencing

Neurodegeneration

The biomarkers of particular interest in AD, as determined using insights from the CAS Content Collection,
are highlighted in Figure 12.
14-3-3β-Synuclein
GAP-43
SNAP-25
NPTX2
neurogranin
NfL
MTBR-tautau

p-tau205
p-tau231
p-tau181Aβp-tau217
Aβ40
Aβ42
1

10

100

Number of documents
Figure 12. AD biomarkers as represented in the CAS Content Collection.

1,000Summary and future directions
The vast global impact combined with the incurable nature of neurodegenerative disorders presents us
with a need for well-directed research. In response to this, investigation into neurodegenerative disorders
is an active and evolving field. Although there are a number of distinct conditions, there are common
areas of interest for future research efforts across the board. Key areas for research in AD, PD, and polyQ
disorders are depicted in Figure 13.

Alzheimer’s disease–

Immunotherapy–

Combination therapy
approaches–

Genetics and personalized
medicine–

Non-pharmacologicalinterventions (cognitive training,
physical exercise, diet, and lifestylemodifications)–

Analysis of large-scale datasets(genetic data, clinical data, imaging
data, and digital biomarkers)

Parkinson’s disease–

PolyQ disorders

Neuroprotective and diseasemodifying therapies–

Stem cell-based approaches–

Precision medicine andpersonalized therapies–

Advances in imaging techniques and biofluid analyses––

Non-motor symptoms andquality of life

Novel strategies to prevent or dissolve toxic
protein aggregates––

Advanced therapies andsurgical interventions

Variable clinical presentation and progressionof polyQ diseases–

The role of non-neuronal cells in disease–

Combination approaches, i.e., targeting
protein aggregation alongside neuroprotective
or anti-inflammatory strategies–

Optimizing clinical trial design to accelerate
the translation of promising therapies to patients–

Digital health and technology
innovations–

Clinical trials and translational
research

Identifying reliable biomarkers for disease onset, progression, and response to treatment

Greater understanding of disease mechanisms and pathogenesis for targeted drug development
Figure 13. Future research directions in the field of neurodegeneration research by disease classification.

While significant challenges remain in the fight against neurodegeneration, sustained efforts in research,
advocacy, and care have the potential to improve outcomes for affected individuals and advance ourcollective efforts toward a future without neurodegenerative diseases.

NEURODEGENERATIVE DISORDERS REPORT | 15

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For more details on the
research landscape ofneurodegeneration,see our publication at
http://link.cas.org/
neurodegenerative

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